Alcoholism has traditionally been
considered a male disease because there are many more alcoholic males
than females.
But a new study by
researchers at Oregon Health & Science University
and the Portland
Veterans Affairs Medical
Center suggests
that women are more prone to brain damage from alcohol abuse than men.
The study led by Kristine
Wiren, Ph.D., associate professor of behavioral neuroscience and
medicine, OHSU School of Medicine, and research biologist, PVAMC
Research Service, found that female mice are more susceptible to
neurotoxic effects of alcohol withdrawal, including significantly
increased brain cell death, than male mice. It also found the gender
difference exists whether the animals are prone to severe withdrawal due
to a genetic predisposition, or resistant to it.
Wiren said she was surprised by the results.
"We designed the experiment to be able to identify gene
expression differences between lines of mice that are genetically
selected for severe alcohol withdrawal compared with mice that are
resistant to alcohol withdrawal," Wiren said. "I thought there would be a
difference between the genders, but I didn't think it would be the most
important thing."
She added, "The
withdrawal severity phenotypes do show some differences, but they're
subtle."
The study appears in
the online edition of the journal Neuropsychopharmacology.
Wiren and Joel Hashimoto, research associate of
behavioral neuroscience at OHSU and the PVAMC Research Service, examined
four groups of selectively bred mice: two female groups, including one
prone to severe withdrawal and one resistant to severe withdrawal, and
two similar male groups. Four control groups also were used.
Using DNA microarray or "gene chip" analysis, a
laboratory process involving advanced robotics that allows large numbers
of genes and their complex interactions to be observed, Wiren and
Hashimoto examined 5,000 genes from the prefrontal cortex, the area of
the brain implicated in complex planning, personality expression and
social behavior, and is involved in withdrawal-related brain circuitry.
They then identified a total of 295 alcohol-regulated genes for each
mouse group.
"We're interested in
that part of the brain because it's important in inhibitory control.
Alcoholics are unable to display good inhibitory control," Wiren said.
After identifying the alcohol-regulated gene pathways,
Wiren and Hashimoto were able to home in on the extent of cell death.
Ten days after alcohol withdrawal, they examined cells in the lateral
parietal cortex area, which is part of the network of brain regions, in
addition to the prefrontal cortex, involved in inhibitory control, and
identified live and dead cells with tissue stains.
"At
this one time point, which is the peak for cell death, we clearly see
females are showing enhanced brain damage compared to the males. So, if
you're female, the cells are dying; if you're a male, the cells are
not," Wiren said. "We don't know the behavioral consequences of that,
though."
What's more, Wiren and
Hashimoto discovered, male brains respond to alcohol withdrawal much
differently, in a potentially reparative manner.
"What
we found in males is that almost 50 percent of the (alcohol-regulated)
genes are involved in the pathway for cleaning things up," Wiren said.
The genes respond with "removal of damaged proteins. The females have
all this apoptosis (cell death) going on, and the males instead may have
repair going on."
Such brain damage may
underlie debilitating cognitive dysfunction and motor deficits observed
in some alcoholics, according to the study. In addition, disruption of
inhibitory functions in the prefrontal cortex may contribute to
excessive drinking and the self-sustaining nature of alcoholism.
"The
results suggest that females are more vulnerable to neurotoxic
consequences of alcohol withdrawal," Wiren noted. "Everyone should be
concerned about chronic alcohol consumption and severe intoxication, but
females may be more vulnerable." This data is "consistent with some
controversial human studies that suggest that females do develop more
brain damage than male alcoholics."
Future
studies, including one funded by the VA, will examine the role that
hormones play in response to alcohol withdrawal, include the possibility
that the male hormone androgen exacerbates cell death in males.
"What
we're looking at now is the involvement of testosterone in mediating
the cell death in females," Wiren said. "Not just in chronic conditions,
but in acute (alcohol consumption) situations, testosterone levels drop
in males. In females, they may rise."
Wiren
also wants to look at a longer withdrawal time course. "Maybe males
show damage at a different time point," she said. "Or it might have
happened earlier and they're showing repair."
The
study was funded by the National Institute on Alcohol Abuse and
Alcoholism of the National Institutes of Health, and all work was
performed at facilities provided by the PVAMC.